A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi

ABSTRACT Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation;...

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Autores principales:	Hyunkyu Sang, Jonathan P. Hulvey, Robert Green, Hao Xu, Jeongdae Im, Taehyun Chang, Geunhwa Jung
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	ATP-binding cassette transporter fungus-specific transcription factor multidrug resistance xenobiotic detoxification cytochrome P450 Sclerotinia homoeocarpa Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c5c7f4d93e0a49fba820e18e001f8878
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spelling	oai:doaj.org-article:c5c7f4d93e0a49fba820e18e001f88782021-11-15T16:00:16ZA Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi10.1128/mBio.00457-182150-7511https://doaj.org/article/c5c7f4d93e0a49fba820e18e001f88782018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00457-18https://doaj.org/toc/2150-7511ABSTRACT Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages. IMPORTANCE Emerging multidrug resistance (MDR) in pathogenic filamentous fungi is a significant threat to human health and agricultural production. Understanding mechanisms of MDR is essential to combating fungal pathogens; however, there is still limited information on MDR mechanisms conferred by xenobiotic detoxification. Here, we report for the first time that overexpression of phase I drug-metabolizing monooxygenases (cytochrome P450s) and phase III ATP-binding cassette efflux transporters is regulated by a gain-of-function mutation in the fungus-specific transcription factor in the MDR strains of the filamentous plant-pathogenic fungus Sclerotinia homoeocarpa. This study establishes a novel molecular mechanism of MDR through the xenobiotic detoxification pathway in filamentous fungi, which may facilitate the discovery of new antifungal drugs to control pathogenic fungi.Hyunkyu SangJonathan P. HulveyRobert GreenHao XuJeongdae ImTaehyun ChangGeunhwa JungAmerican Society for MicrobiologyarticleATP-binding cassette transporterfungus-specific transcription factormultidrug resistancexenobiotic detoxificationcytochrome P450Sclerotinia homoeocarpaMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP-binding cassette transporter fungus-specific transcription factor multidrug resistance xenobiotic detoxification cytochrome P450 Sclerotinia homoeocarpa Microbiology QR1-502
spellingShingle	ATP-binding cassette transporter fungus-specific transcription factor multidrug resistance xenobiotic detoxification cytochrome P450 Sclerotinia homoeocarpa Microbiology QR1-502 Hyunkyu Sang Jonathan P. Hulvey Robert Green Hao Xu Jeongdae Im Taehyun Chang Geunhwa Jung A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
description	ABSTRACT Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages. IMPORTANCE Emerging multidrug resistance (MDR) in pathogenic filamentous fungi is a significant threat to human health and agricultural production. Understanding mechanisms of MDR is essential to combating fungal pathogens; however, there is still limited information on MDR mechanisms conferred by xenobiotic detoxification. Here, we report for the first time that overexpression of phase I drug-metabolizing monooxygenases (cytochrome P450s) and phase III ATP-binding cassette efflux transporters is regulated by a gain-of-function mutation in the fungus-specific transcription factor in the MDR strains of the filamentous plant-pathogenic fungus Sclerotinia homoeocarpa. This study establishes a novel molecular mechanism of MDR through the xenobiotic detoxification pathway in filamentous fungi, which may facilitate the discovery of new antifungal drugs to control pathogenic fungi.
format	article
author	Hyunkyu Sang Jonathan P. Hulvey Robert Green Hao Xu Jeongdae Im Taehyun Chang Geunhwa Jung
author_facet	Hyunkyu Sang Jonathan P. Hulvey Robert Green Hao Xu Jeongdae Im Taehyun Chang Geunhwa Jung
author_sort	Hyunkyu Sang
title	A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
title_short	A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
title_full	A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
title_fullStr	A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
title_full_unstemmed	A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi
title_sort	xenobiotic detoxification pathway through transcriptional regulation in filamentous fungi
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c5c7f4d93e0a49fba820e18e001f8878
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A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi

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